As it is known, neurodegenerative diseases are progressive, devastating, chronic age related disorders. With increasing life expectancy the incidence of these age-related diseases will be dramatically increasing in the next decades. The treatment of these maladies currently is only symptomatic, causal therapy does not exist due to the largely unknown cause(s) of these multietiological diseases. Though the etiology and the actual localization of cell damage and loss in the central nervous system (CNS) in these disorders—like Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Neuropathies, Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS)—may differ, there are many common points in the disease development, and in the intracellular events.
Although great progress has been made in the symptomatic treatment of a number of neurodegenerative disorders, there is still a huge, unmet need for pharmacological and biopharmacological treatments that will slow and possibly halt the progress of these diseases.
AD is the most common neurodegenerative disease and the most common form of dementia (responsible for about 80% of all cases). AD is characterized by memory loss, language deterioration, impaired visuospatial skills, poor judgment, indifferent attitude, but preserved motor function.
Alzheimer's disease symptoms appearing first as memory decline and, over several years, destroying cognition, personality, and ability to function. Confusion and restlessness may also occur. Amyloid plaques and neurofibrillary tangles in the brain are the distinctive characteristics of the disease, there is also a loss of nerve cells in areas of the brain that are vital to memory and other mental abilities. The disease usually begins after age 60, and risk goes up with age. While younger people also may get Alzheimer's, it is much less common. About 3 percent of men and women ages 65 to 74 have AD, and nearly half of those age 85 and older may have the disease.
There is no cure today for Alzheimer's disease and patients usually live about 8 to 10 years from the time of diagnosis. There are a number of drugs on the market, which may help prevent some symptoms from worsening for a limited time. In addition, some medicines may help control behavioral symptoms of AD.
Presently there are four drugs approved by the FDA to treat the symptoms of mild-to-moderate AD. These medications are known as cholinesterase inhibitors, which research suggests, act to prevent the breakdown of acetylcholine, a brain chemical believed to be important for memory and thinking. Although none of these medications stops the disease itself, they can help delay or prevent symptoms from becoming worse for a limited time and may help maintaining independence for a longer period of time. As the disease progresses, the brain produces less and less acetylcholine, and the medications may eventually lose their effect. Exelon and Reminyle are the most successful and marketed drugs of this class (See: Neurodegenerative Disorders: The world market 2002-207; a Visiongain Report; VISIONGAIN™, 2003; see also: Terry A V and Buccafusco J J: The cholinergic hypothesis of age and Alzheimer's disease related cognitive deficits: recent challenges and their implications for novel drug development; The Journal of pharmacology and experimental therapeutics, 306: 821-27, 2003; and Cummings J L: Use of cholinesterase inhibitors in clinical practice: evidence based recommendations; Am J Geriatr Psychiatry 11: 131-45, 2003.).
Other treatment trials for AD include the Ginko biloba extract—as an antioxidant, but the studies so far do not demonstrate clear efficacy among AD patients.
Nonsteroidal anti-inflammatory agents tested until today did not proved to be effective.
Newly approved in Europe, Ebixa (Memantine), a non-specific NMDA antagonist that is being marketed by Merz and Lundbeck, is set to compete with the reputed gold standard in treatment, Aricept. Clinical trials have yielded positive results thus far (Mintzer J E: The search for better noncholinergic treatment options for Alzheimer's disease, J Clin Psychiatry 64, suppl 9:18-22, 2003; and Reisberg B et al.: Memantine in moderate to severe Alzheimer's disease, N Engl J Med 348:1333-41, 2003.). Another, until now controversial approach was the immunization as to develop drugs that is able to decreasing amyloid beta production, and clearing the amyloid deposits by immunization.
PD is the second neurodegenerative disorder in incidence and importance. Parkinson's occurs when certain brain cells in an area of the brain known as the substantia nigra die or become impaired. The exact cause of neuronal death is unknown, but oxidative stress and mitochondrial electron transport chain dysfunction—especially the decreased activity of complex I—is widely accepted. These neurons produce an important chemical known as dopamine, a chemical messenger responsible for transmitting signals between the substantia nigra and the corpus striatum.
Symptoms of Parkinson's disease include the followings: tremor, or the involuntary and rhythmic movements of the hands, arms, legs and jaw, is a primary feature. Classically, tremor appears while the individual is at rest and improves with intentional movement; Gradual loss of spontaneous movement, which often leads to a variety of problems such as “freezing”, decreased mental skill or quickness, voice changes, and decrease facial expression; Muscle rigidity, or stiffness of the limbs, occurs in all muscle groups but is most common in the arms, shoulders or neck; Postural instability, or a stooped, flexed posture with bending at the elbows, knees and hips; Gradual loss of automatic movement, including eye blinking and decreased frequency of swallowing; Unsteady walk; Depression and dementia.
Patients of the disease currently have a large number of treatment options and this number will also be rising steadily over the next 10 to 15 years. The first effective therapy for the treatment of Parkinson's, carbidopa/levodopa (Sinemet-Bristol Myers Squibb), was introduced in 1970 and revolutionized treatment of the disease. The therapy proved very effective in controlling symptoms such as tremor, bradykinesia, balance, and rigidity. However, dyskinetic side-effects and reduced effect with prolonged treatment proved the need for alternative treatments and/or ancillary drugs to offset side-effects. Dopamine agonists, which entered the market in the 1980s, filled this need. These drugs have proved effective as a type of dopamine regulator and as a monotherapy in delaying the need for carbidopa/levodopa therapy in newly diagnosed Parkinson's patients. Other newly developed therapies such as COMT inhibitors, anticholinergics, and selegiline/deprenyl have also had an effect, although less marked, on the PD market (See: Neurodegenerative Disorders: The world market 2002-207; a Visiongain Report; VISIONGAIN™, 2003.).
Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's disease, is a rapidly progressive, invariably fatal neurological disease that attacks the nerve cells (neurons) responsible for controlling voluntary muscles. The disease is the most common motor neuron disease, which is characterized by the gradual degeneration and death of motor neurons (Rowland L P, Schneider N A: Amyotrophic lateral sclerosis. N Engl J Med 344:1688-1700, 2001.). Motor neurons are nerve cells located in the brain, brainstem, and spinal cord that serve as controlling units and vital communication links between the nervous system and the voluntary muscles of the body. Messages from motor neurons in the brain (called upper motor neurons) are transmitted to motor neurons in the spinal cord (called lower motor neurons) and from them to particular muscles. In ALS, both the upper motor neurons and the lower motor neurons degenerate or die, ceasing to send messages to muscles. Unable to function, the muscles gradually weaken, waste away (atrophy), and twitch (fasciculations). Eventually, the ability of the brain to start and control voluntary movement is lost. Most people with ALS die from respiratory failure, usually within 3 to 5 years from the onset of symptoms.
The cause of ALS is not known. However, an important step toward answering that question came in 1993 when scientists discovered that mutations in the gene that produces the SOD1 enzyme were associated with some cases of familial ALS (Rosen D R et at: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 362: 59-62, 1993.). This enzyme is a powerful antioxidant that protects the body from damage caused by free radicals. Free radicals are highly unstable molecules produced by cells during normal metabolism (the major source is the mitochondrion). If not neutralized, free radicals can accumulate and cause random damage to the DNA, membrane lipids and proteins within cells. Although it is not yet clear how the SOD1 gene mutation leads to motor neuron degeneration, researchers have theorized that an accumulation of free radicals may result from the faulty functioning of this gene.
Although many distinct features are present in the neurodegenerative diseases, common feature is, the cell loss, gradual and progressive degeneration of certain central nervous system areas. Imbalance in reactive oxygen species (ROS) production and neutralization capacity is increasing with ageing, and neurodegenerative diseases worsen this. The role of SOD in ALS was described above as a powerful antioxidant that protects the brain from damage caused by free radicals. In Parkinson's disease ROS is generated by autooxidation during normal dopamine metabolism or by the action of monoamine oxidase (Lev N et al.: Apoptosis and Parkinson's disease; Progress in Neuro-Psychopharmacology and Biological psychiatry 27: 245-50, 2003.). In AD the exact initiating events leading to disease development are complex, but it is widely accepted that neuronal death is mediated partly by free radical injury (Pratico D and Delanty N: Oxidative injury in diseases of the central nervous system: Focus on Alzheimer's disease, Am J Med 109: 577-85, 2000.)
Currently the only proven therapy for patients suffering from ALS, Riluzole, extents survival by approximately 3 months. (Miller, R. G., Mitchell, J. D., Lyon, M. & Moore, D. H. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane. Database. Syst. Rev. CD001447 (2002)). Therefore, the identification of new therapeutic strategies to employ for the treatment of ALS remains a priority.
It is known from WO 97/16439 that several types of hydroxylamine derivatives enhance chaperon expression in cells exposed to a physiological stress and are useful in the treatment of diseases connected with the function of chaperon system. Various new categories of hydroxylamine derivatives are disclosed in this published patent application. A certain class of hydroximic acid halides N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride belongs to is also defined but N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride is not mentioned explicitly.
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride is first disclosed and claimed in WO 00/50403 as an eminent species capable of lowering insulin resistance. As stated, it is useful in the treatment of a series of chronic diabetic complications especially rethinopathy, neuropathy and nephropathy and pathological decrease of neuroregeneration caused by diabetes while reducing insulin resistance in the patient. The chemical properties of this compound and details of the synthetic procedure of its preparation are also described in the said paper.
An other utility of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride in diabetic therapy especially in the therapy of type II (non-insulin dependent, NIDDM) diabetes is described in WO 03/026653.
The invention disclosed here relates to an orally applicable antihyperglycemic composition containing a combination of metformin and N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride as active principle. The outstanding antihyperglycemic effect is based on synergism deriving from the combination of the two active agents.
None of the patent publications relating to N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride suggests the use of this compound outside of the diabetes therapy.